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Clavulanic Acid Production by Streptomyces Clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing

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Clavulanic Acid Production by Streptomyces Clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing antibiotics Review Clavulanic Acid Production by Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing Víctor A. López-Agudelo 1 , David Gómez-Ríos 2 and Howard Ramirez-Malule 1,* 1 Escuela de Ingeniería Química, Universidad del Valle, A.A., Cali 25360, Colombia; [email protected] 2 Grupo de Investigación en Simulación, Diseño, Control y Optimización de Procesos (SIDCOP), Departamento de Ingeniería Química, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín 050010, Colombia; [email protected] * Correspondence: [email protected]; Tel.: +57-2-3212100 (ext. 7367) Abstract: Clavulanic acid (CA) is an irreversible β-lactamase enzyme inhibitor with a weak antibac- terial activity produced by Streptomyces clavuligerus (S. clavuligerus). CA is typically co-formulated with broad-spectrum β-lactam antibiotics such as amoxicillin, conferring them high potential to treat diseases caused by bacteria that possess β-lactam resistance. The clinical importance of CA and the complexity of the production process motivate improvements from an interdisciplinary standpoint by integrating metabolic engineering strategies and knowledge on metabolic and regulatory events through systems biology and multi-omics approaches. In the large-scale bioprocessing, optimization of culture conditions, bioreactor design, agitation regime, as well as advances in CA separation and purification are required to improve the cost structure associated to CA production. This review presents the recent insights in CA production by S. clavuligerus, emphasizing on systems biology approaches, strain engineering, and downstream processing. Citation: López-Agudelo, V.A.; Gómez-Ríos, D.; Ramirez-Malule, H. Keywords: clavulanic acid; Streptomyces clavuligerus; systems biology; strain engineering; Clavulanic Acid Production by downstream processing Streptomyces clavuligerus: Insights from Systems Biology, Strain Engineering, and Downstream Processing. Antibiotics 2021, 10, 84. https://doi.org/10.3390/antibiotics 1. Introduction 10010084 The accessibility to effective treatment alternatives of infectious diseases depends on the availability of appropriate antibiotic compounds in the market. Efficient antibiotic Received: 23 December 2020 production is crucial for health systems worldwide, especially in outbreaks, epidemics, Accepted: 12 January 2021 and health emergencies, in which the antibiotic supply chain can be put under pressure. Published: 18 January 2021 Additionally, the acquired antibiotic resistance phenomenon became a global concern as it may increase the vulnerability of health systems [1]. The antibiotic resistance phe- Publisher’s Note: MDPI stays neutral nomenon emerged along with the antibiotic era [2,3]. Years before penicillin was used at with regard to jurisdictional claims in global scale, a penicillinase enzyme able to inactivate penicillin was discovered in bacteria published maps and institutional affil- extracts [4]. Antibiotic resistance has forced humanity to maintain an endless search for iations. new and more powerful antibiotics. In this regard, the pharmaceutical industry plays a key role in the development of effective treatments against such multidrug-resistant bacteria [1]. Since the discovery of benzylpenicillin in the 1920s, the class of compounds referred to as β-lactam antibiotics has been the most extensively used antibiotics. Nev- Copyright: © 2021 by the authors. ertheless, a significant number of different antibiotic compounds (such as carbapenems, Licensee MDPI, Basel, Switzerland. cephamycins, cephalosporins, and monobactams) has been developed and implemented in This article is an open access article the clinical practice as a strategy to evade the acquired resistance [5]. The new combinations distributed under the terms and of antibiotics are aimed to increase their spectrum of activity and overcome the resistance conditions of the Creative Commons barriers developed by the bacteria. In order to mitigate the bacterial resistance to β-lactam Attribution (CC BY) license (https:// antibiotics, several compounds have been identified as β-lactamase inhibitors. Those com- creativecommons.org/licenses/by/ pounds can irreversibly inactivate the β-lactamases allowing the β-lactam antibiotics to 4.0/). Antibiotics 2021, 10, 84. https://doi.org/10.3390/antibiotics10010084 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, 84 2 of 26 act against the infection. The main β-lactamase inhibitors are Sulbactam, Tazobactam, and clavulanic acid (CA) as clavulanate salt. CA is a β-lactam compound with modest antibiotic activity but high inhibition capacity of β-lactamase enzymes. The CA molecule is an analog of the penicillin nu- cleus, in which the characteristic sulfur atom has been substituted by an oxygen atom. CA is one of the so-called “clavam metabolites” produced by the filamentous bacterium Streptomyces clavuligerus (S. clavuligerus); most of those metabolites have the characteristic fused bicyclic β-lactam/oxazolidine ring. Nevertheless, the CA molecule (Figure1) has 3R, 5R stereochemistry, opposite to the 3S, 5S configuration present in other clavam metabo- lites, which do not exhibit β-lactamase inhibition activity, although some of them have antibacterial or antifungal properties [6]. In addition to the stereochemistry, the inhibitory effect of CA has been explained by the presence of the β-lactam/oxazolidine ring that bonds irreversibly with a serine residue in the catalytic center of the β-lactamase enzyme, thus rendering it inactive [7]. Currently, CA is used in combination with other β-lactam an- tibiotics as an effective treatment against several clinical syndromes including pneumonia and exacerbations of chronic obstructive pulmonary disease, complicated intra-abdominal infections, acute infectious diarrhea, urinary tract infections, pharyngitis, surgical, wound, and skin infections [8]. Some of them are caused by resistant pathogenic bacteria already included in the World Health Organization priority list: Escherichia coli, Staphylococcus aureus, Neisseria gonorrhoeae, Streptococcus pneumonia, and all Enterobacteriaceae and Klebsiella species [1]. Figure 1. Clavulanic acid (CA) structure. Red and blue C atoms correspond to those coming from C-3 and C-5 precursors, respectively. * Stereochemical centers on CA structure. CA is produced worldwide at large scale by several pharmaceutical companies, and it is also prescribed in more than 150 countries [9]. CA has a relatively limited market avail- ability and a middle–high cost for the health system, especially in the developing countries when compared with the income level, being quite inaccessible for people without health insurance. The cost of CA is mainly related to the complexity of the production process, the current uncertainties about the regulatory elements controlling the CA biosynthetic gene cluster and the intellectual property associated with its production [6]. Despite the significant number of studies related to CA production in S. clavuligerus submerged cultiva- tions, low titers (~1 g·L−1) are still obtained when using a wild type strain. The productivity of CA production bioprocess is also compromised by the downstream processing: CA separation from fermentation broths and precipitation as clavulanate salt. This review presents a holistic overview of CA production process: CA biosynthesis; CA production in S. clavuligerus submerged cultivation; recent advances in strain engineering; and elu- cidation of regulatory elements controlling CA production, systems biology approaches, and downstream processing (Figure2). Antibiotics 2021, 10, 84 3 of 26 Figure 2. Holistic overview of the CA production process. 2. Overview of CA Biosynthesis in S. clavuligerus The Streptomyces genus produces a wide variety of secondary metabolites with antimi- crobial activity (approximately two-thirds of which occur naturally) [10]. In 1971, Nagarajan et al. [11] reported a new Streptomycete species as producer of two cephalosporin com- pounds. This new species was then named and described as S. clavuligerus by Higgens and Kastner, also in 1971 [12]. Later, in 1976, Howarth and Brown [13] described the CA chemi- cal structure, which was elucidated via spectroscopic and X-ray analyses and reported as a novel fused β-lactam compound with a significant inhibitory activity of β-lactamases. In 1977, Reading and Cole described the cultivation conditions of S. clavuligerus to produce CA and the spectrometric method for CA detection [7]. In 1941, the biochemist Selman Waskman described the most accepted definition of “antibiotic” as a small molecule made by microorganisms that inhibits the growth of another microorganism. During the “golden age” of antibiotics, approximately 70–80% of the antibiotics discovered came from Streptomycetes, but the evolutionary reason for the development of antibiotic biosynthetic capacity of soil bacteria and its ecological role are still unknown. Soil bacteria are not very efficient at up-taking nutrients, and their growth rate is considerably low in comparison with other bacteria and fungi. A plausible hypothesis that iswidely accepted implies that antibiotics secretion allows the producer to control the organisms competing for the same nutritional resources in a hostile multispecies environment [2,14]. This is consistent with the secondary nature of antibiotics secretion un- der nutritional restriction. However, the antibiotic compounds at very low concentrations can modulate
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